When Peter A. Prieto, M.D., M.P.H., was a young clinical fellow at the National Cancer Institute, he had one of those “aha!” moments that turned out to define his mission.
He was on a team that was treating a man who had advanced melanoma, which had spread from the leg to his liver and bones. The treatment was an experimental immunotherapy — an approach known as adoptive cell therapy using tumor infiltrating lymphocytes (TILs). The TILs, which are cancer-fighting T-cells, are extracted from the tumor, expanded in a laboratory, and then infused back into the patient.
But something unexpected and dramatic happened during that case, Prieto says: Before doctors could reintroduce the engineered TILs back into the body, the man’s cancer began to melt away.
“We thought it was a bit of a fluke, but we repeated his imaging in three months, and his tumors continued to shrink. Later, they completely disappeared,” Prieto says. “This is an extremely rare occurrence, a spontaneous regression, but it tells us about the body’s ability to use the immune system to completely eradicate cancer.”
Prieto believes that something probably occurred during the surgery to remove the man’s metastatic liver tumor that woke the immune system.
“If we could only capture, define, and replicate exactly what happened — that would be a major breakthrough,” he says.
Immunotherapy is rife with unknowns like this. While often frustrating, these unknowns are also among the most interesting aspects of this field. Why does it work the way it does? Why doesn’t it unfold the same way in every patient?
Although in concept it is not new, immunotherapy has stirred a lot of excitement lately as a cancer treatment. New studies this spring suggested that in lung cancer, for example, a combination of immunotherapy and chemotherapy should be the new standard of care. And scientists have also demonstrated some success in blood cancers such as lymphoma and leukemia. In fact, recently, the Wilmot Cancer Institute and other centers across the U.S. began offering a type of immunotherapy, called CAR T-cell therapy, to treat blood cancers and continue to study CAR T-cells for other malignancies.
But scientists are still working to figure out why it hasn’t been as effective in solid tumors such as prostate, ovarian, and colon cancer, and why the responses to immunotherapy vary significantly.
Inspired by his previous experience, Prieto has joined with Minsoo Kim, Ph.D., to launch a TIL investigation that they hope will solve some of the many mysteries about immunotherapy.
“Not all cancers are the same and not all immune systems are the same. So we need to find biomarkers, especially for patients who do not respond well,” says Kim, a Dean’s Professor of Microbiology and Immunology at the University of Rochester Medical Center and director of the Tumor Immunotherapy Research Program at Wilmot. “What is it that dampens the response, and how can we change it?”
Kim also has a longtime interest in the body’s immune response to foreign invaders. He invented an optical, LED-guided system to steer cancer-fighting immune cells toward tumors. In a study published last year by Nature Communications, Kim showed that in mice with melanoma, the light therapy system could assist immunotherapy drugs in activating a response to cancer.
“Both Peter and I have the same concerns about the need to take immunotherapy to the next level,” Kim says. “Immunotherapy only works in about 40 percent of patients and we need to find ways to apply it to more people. It’s exciting to be developing platforms that can get us to that point.”
A highly personalized approach
They will begin with a TIL platform, based on Prieto’s experience at the NCI, where he earned a coveted, three-year fellowship to work with Steven A. Rosenberg, M.D., Ph.D., one of the fathers of immunotherapy and the first doctor to perform gene therapy as a form of cancer treatment in humans. Rosenberg pioneered the use of TIL therapy in melanoma, and has gone on to lead further development of immunotherapy with new technologies.
TILs are the immune cells that race from the blood and hibernate in tumors, signaling the immune system to try to attack the cancer.
Prieto primarily treats melanoma, sarcoma, and breast cancer patients, and joined Wilmot last year as an assistant professor of Surgery after being recruited from the MD Anderson Cancer Center in Texas, which specializes in TIL therapy. He is planning to bring this highly personalized TIL therapy to Wilmot patients with advanced melanoma.
He and Kim initially will focus on the best ways to grow and expand extracted patient T-cells, a specialized skill that requires strict lab protocols.
Once they begin offering the treatment, Kim will simultaneously study the immune environment around the tumor in the patient samples, and its interaction with cancer cells — and then connect and compare his laboratory observations with the real-life outcomes and experiences of Prieto’s patients.
Scientists are also investigating the critical role of the neighborhood of cells and tissues around the cancer cells, known as the microenvironment.
Other research at Wilmot and elsewhere has proven the importance of the microenvironment’s role in many cancers. For example, manipulating it can make it more favorable for identifying cancer cells and can set the stage for successful destruction of tumors, research suggests.
But untangling the actions of the immune cells and other cells around each tumor is a challenge. As cancer spreads, for example, new tumors with characteristics different from the original tumor spawn new immune environments. On average, there’s only a 50-percent similarity between the primary tumor and the metastatic tumor, Prieto says.
In the pursuit of the microenvironment’s role in melanoma and other solid tumors, the duo will work closely with Prieto’s mentor in Rochester, David Linehan, M.D., director of clinical operations at Wilmot, and the Seymour I. Schwartz Professor and Chair of Surgery at URMC who is also a pioneer in pancreatic cancer immunotherapy.
“Ultimately at Wilmot, “ Prieto says, “we would like far more patients to be eligible for and to respond to this fascinating new form of cancer treatment.”